Alcohol abuse is a serious illness with detrimental effects on the individual and society. Particularly, binge drinking is a rampant and growing problem with approximately 83,000 deaths attributable to excessive alcohol drinking and an economic cost to the United States of $223.5 billion in 2006 (Bouchery et al, 2011). A multitude of family, twin, and adoption studies have demonstrated a genetic component to alcohol addiction, which may lead to increased risk of addiction and altered response to treatments. Converging evidence between human and rodent literature suggests MPDZ/ Mpdz, a gene encoding the multiple PDZ domain containing protein MPDZ, may be one such gene that contributes to increased vulnerability for alcoholism. In mice, my lab has demonstrated that Mpdz is highly expressed throughout the brain, and reduced expression leads to increased ethanol (alcohol - these terms will be used interchangeably throughout the proposal) withdrawal severity and reduced voluntary consumption in a two-bottle choice paradigm, and vice versa. The goal of this project is to extend the analyses to a paradigm which produces excessive levels of alcohol intake to better model the human condition. Thus, the goal is to determine Mpdz's role a model of binge ethanol drinking, to identify functionally related transcripts that may elucidate a signaling system dependent on Mpdz that mediates drinking, and to assess the role of Mpdz in a discrete brain region on the genetic correlative relationship between ethanol drinking and withdrawal. Thus, Aim 1 will seek to determine how Mpdz expression influences excessive ethanol consumption by assessing Mpdz heterozygotes (Mpdz+/-) and wild type (WT) littermates using the two bottle drinking in the dark (2B-DID) paradigm to assess binge drinking, and whether or not both genotypes will drink to behaviorally and physiologically relevant intoxication levels. Further, using Mpdz+/- and WT mice, Aim 2 of this proposal will begin to identify additional gene transcripts altered by Mpdz expression. This Aim will seek to determine how differential Mpdz expression may alter the expression of functionally related transcripts and how this may be impacted by ethanol binge drinking. This is expected to elucidate the signaling systems (i.e., functionally related and/or compensatory) affected by Mpdz that could influence ethanol drinking behavior. Finally, Aim 3 will employ RNA interference to selectively knockdown Mpdz expression in the dorsal lateral striatum, a region believed to importantly mediate ethanol consumption, of B6 mice to determine how Mpdz within this region mediates alcohol drinking and related ethanol withdrawal severity. The novel and innovative project proposed here will provide conclusive evidence that Mpdz is a genetic contributor to risk for binge drinking, putatively through the dorsal lateral striatum, and related ethanol withdrawal severity.